1. Field of the Invention
This invention is directed to capsules which are used as a storage medium for pharmaceutical powders. In particular, the invention pertains to a method of treating a hard capsule used to store a pharmaceutical powder wherein the powder requires delivery via inhalation, so as to enhance delivery of the pharmaceutical powder to the patient. The invention also relates to a hard capsule treated according to the above method.
2. Description of Related Art
Capsules are frequently used as a storage medium for finely divided pharmaceutical powders containing drug molecules requiring delivery via inhalation. The capsules consist of two halves that are separated, filled with the pharmaceutical powder and closed. Often, the capsule is a hard gelatin capsule, such as those referred to in Niemi, Jr. et al., Biomedical Sciences Instrumentation 16:39-43 (April 1980); Vidgren et al., International Journal of Pharmaceutics 42:211-216 (1988); Okumura et al., S.T.P. Pharma Sciences 4(1):45-49 (1994); U.S. Pat. Nos. 4,681,752; 3,173,840; and 4,500,358. Hard cellulose and plastic capsules suitable for storing pharmaceutical powders are also available commercially.
There has been an increase in the number of therapeutic proteins which have shown promise for administration by aerosol to the lungs of the patient for either local action or systemic absorption. For a review of these, see Niven R. W., Pharm Tech. 17:72-82 (1993).
For example, recombinant human deoxyribonuclease I (rhDNase) is administered as an aerosol to the lungs of patients suffering from cystic fibrosis. rhDNase is able to cleave DNA present in the thick, viscous secretions in the airways of the lungs of the patient thereby reducing sputum viscosity (see, e.g., Shaket al., Proc. Nat. Acad. Sci. 87:9188-92 [1990]; Aitken et al., Jama 267:1947-1951 [1992]; and Hubbard et al., New. Eng. J. Med. 326:812-815 [1992]).
Vogelmeier et al., J. Appl. Physiol. 69(5):1843-1848 (1990) and Hubbard et al., Pro. Nat. Acad. Sci. 86:680-684 (1989) discuss the neutrophil inhibitors; secretory leukoprotease inhibitor (SLPI) and alpha-1-antitrypsin, and their therapeutic potential when administered by aerosol via the respiratory route. U.S. Pat. No. 5,230,884 discloses an aerosol formulation for delivery of insulin to a patient's lungs.
Capsules containing drugs are generally used in conjunction with dry powder inhaler (DPI) devices such as the Spinhaler.TM., Rotahaler.TM. and Inhalator.TM.. Prior to administration of the pharmaceutical powder, the capsules are cut or pierced so as to enable the pharmaceutical powder to be inhaled by the patient. Where the drug is to be delivered to the upper respiratory tract (i.e., intranasal), the drug particles generally need to be between about 20-100 .mu.m in size. Where administration is to the lower respiratory tract (i.e., intrapulmonary), the drug particles generally need to be less than about 5 .mu.m in size.
In order to improve the flow properties of the pharmaceutical powder (for ease of filling the capsules during manufacture and emptying the capsules during inhalation by the patients), the fine particles to be placed in the capsule can be "pelletized" into larger agglomerates or a physical blend of the finely divided drug powder with a carrier molecule can be made by mixing the powder containing the fine drug-containing particles with the coarser carrier. The carrier is typically lactose or mannitol and also acts as a bulking agent for low dose drugs. See, for example, U.S. Pat. No. 5,254,330. The fine drug containing particles adhere to the surface of the much larger carrier particles. Consequently, the total blend has the improved flow properties of the larger carrier particles.
Regardless of whether the drug is pelletized or attached to the carrier particle, it must become available again in the form of fine particles prior to entry into the patients' respiratory tract. This is typically achieved by spinning and shaking the capsule in the DPI and thereby breaking up the powder by various baffles and grids. The dispersed pharmaceutical compound is then inhaled into the lungs of the patient.
During the manufacture of capsules such as hard gelatin, cellulose and plastic capsules, their internal surfaces become coated in mould release lubricants. This is because the manufacturing process involves dipping mould pins into molten capsule-forming material, removing the pins and allowing the capsule-forming material to harden. The hard capsule shells are then removed from the pins. In order to remove the shells without damaging them, it is essential that the mould pins be lubricated. However, this lubricant tends to coat the inside surface of the capsule.
The inventors have discovered that this is problematic insofar as it reduces the effective amount of the pharmaceutical compound reaching the respiratory tract of the patient. For example, the inventors have found that formulations containing one milligram of recombinant human DNase can leave as much as 0.5 to 0.6 milligrams of recombinant human DNase adhering to the capsule walls. It was proposed that the retention of the drug in the capsule could be reduced using a lubricant composition considered to cause less adhesion. However, as demonstrated in Example 1 disclosed herein, capsule adhesion was not significantly reduced as a consequence of using an alternative lubricant composition.
Accordingly, it is an object of the present invention to overcome the problem associated with the retention of pharmaceutical powders to capsules, which problem was first recognized by the inventors of the present application. Overall, this method reduces drug loss as a consequence of administration by inhalation.
It is a further object of the invention to reduce the variation in the dosages of a pharmaceutical compound administered to different patients, particularly where the pharmaceutical compound is administered via inhalation at low dosages.
Other objects and advantages of the present invention will become apparent to one of ordinary skill in the art.